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About
Prospective, multi-center, randomized, open label comparative Phase III study in patients with intermediate to high-risk (as defined in the SURVIVE trial) HER2-positive or HER2-low early breast cancer, who participate in the SURVIVE trial and experience a molecular relapse, as assessed based on a positive circulating tumor DNA (ctDNA) result, with 2:1 allocation to:
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Patients will be eligible for study participation if they comply with the following criteria:
Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
Females or males, ≥ 18 years and ≤ 75 years of age.
Invasive breast carcinoma as revealed by local pathology that is either:
Complete resection of the tumor with resection margins free of invasive carcinoma (R0).
Participation in the SURVIVE study and evidence of molecular relapse (as assessed based on a positive ctDNA result obtained in the SURVIVE-study)
No evidence of metastatic relapse as revealed by a CT-scan (Abdomen/Chest) and a SPECT bone scan that must be performed within 8 weeks before randomization (M0).
Completion of surgery, (neo-)adjuvant chemotherapy (if applicable) and radiation therapy (if applicable, whichever occurred last) at least 6 months before randomization.
Adjuvant/Postneoadjuvant treatment with Trastuzumab, Pertuzumab, T-DM1, Capecitabine, Pembrolizumab, and Olaparib must be discontinued upon randomization into Arm A (treatment with trastuzumab deruxtecan). The washout periods (see Table 2) must be complied with. Endocrine therapy (i.e. Tamoxifen, Letrozol, Anastrozol, Fulvestrant or Exemestane) can be administered simultaneously to treatment with trastuzumab deruxtecan.
Known HR status, per local laboratory assessment, as defined by ASCO-CAP guidelines (≥1%): HR-positive status defined by either positive estrogen receptor (ER) and/or positive progesterone receptor (PR) status. HR-negative status defined by both known negative ER and known negative PR
Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to randomization
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening
Adequate organ and bone marrow function within 28 days before randomization as described in table 1. Organ and bone marrow function criteria must also be met when laboratory tests are repeated within 3 days before Cycle 1 Day 1. Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 2 weeks prior to the day on which marrow function is assessed.
Adequate treatment washout period before treatment with trastuzumab deruxtecan (in case of randomization into cohort A), defined in table 2.
Female subjects: Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of Investigational Medicinal Product (IMP).
Male subjects: Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of IMP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception throughout this period, as described in section 5.5.1. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of randomization/enrolment, throughout the study and for 4 months after the last dose of IMP. Preservation of sperm should be considered prior to enrolment in this study.
Exclusion criteria
Stage IV (metastatic) breast cancer.
Patients with a history of any secondary primary malignancy are ineligible with the following exceptions:
Prior treatment with T-DXd.
Combination of T-DXd with any other anti-cancer treatment is not permitted, except for endocrine therapy.
Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
Patients with a medical history of myocardial infarction (MI) within 6 months before first exposure to study intervention, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out MI.
Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG.
History of (non-infectious) Interstitial lung disease (ILD) / pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
Active primary immunodeficiency, known uncontrolled active HIV infection or active hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects should be tested for HIV prior to randomization/enrolment if required by local regulations or institutional review board (IRB)/ethics committee (EC).
Lung criteria:
Participants with past or resolved HBV infection are eligible only if they meet all of the following criteria:
Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of T-DXd.
Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP.
Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline.
Note: Toxicities related to endocrine therapy should be documented but does not lead to exclusion of patient from the study.
Also, subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to >Grade 2 for at least 3 months prior to first exposure to study intervention and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, such as:
i. Hypothyroidism/hyperthyroidism ii. Type 1 diabetes iii. Hyperglycemia iv. Adrenal insufficiency v. Adrenalitis vi. Skin hypopigmentation (vitiligo)
Known allergy or hypersensitivity to study treatment or any of the study drug excipients.
History of severe hypersensitivity reactions to other monoclonal antibodies.
Pregnant or breastfeeding female patients, or patients who are planning to become pregnant.
Primary purpose
Allocation
Interventional model
Masking
180 participants in 2 patient groups
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Central trial contact
Wolfgang Janni, Prof. Dr. med.
Data sourced from clinicaltrials.gov
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